The candidate is a junior investigator in pediatric nephrology with advanced training in clinical epidemiology. Her research is focused on the extra-skeletal actions of vitamin D and the unique challenges of managing vitamin D deficiency in patients with glomerular diseases complicated by nephrotic-range proteinuria. Vitamin D deficiency may be an important modifiable risk factor for renal disease progression and complications in these patients. Many small studies documented very low total 25-hydroxyvitamin D [25(OH)D] levels in nephrotic patients, but the underlying pathophysiology is poorly understood. Further, the safety and efficacy of supplementation in this sizeable patient population must be determined in order to prevent both potential toxicity and under-treatment. The candidate's preliminary work demonstrated that glomerular disease, particularly focal segmental glomerulosclerosis (FSGS), was an independent risk factor for low total and free 25(OH) D levels and vitamin D-binding protein (DBP) in children with chronic kidney disease. These findings implicate impaired tubular reabsorption of 25(OH) D-DBP complexes and/or increased vitamin D catabolism. The proposed project comprises: (1) an ancillary cross-sectional study of 450 participants in the NIH-funded Nephrotic Syndrome Study Network (NEPTUNE) and (2) a pilot study of cholecalciferol supplementation in 35 children and young adults with FSGS. Leveraging NEPTUNE's unique repository of standardized histopathology data, this work will be the first to determine the association between tubulointerstitial injury an vitamin D metabolites and to delineate the impact of fibroblast growth factor 23-promoted catabolism on vitamin D levels in these patients. The supplementation study will address the safety and efficacy of calciferol supplementation in proteinuric FSGS patients and use novel translational measures of innate immunity and intra-renal inflammation to assess the response to supplementation. The findings of this work will be critical to the design and conduct of subsequent vitamin D trials, and to the development of supplementation guidelines. The candidate's comprehensive career development plan includes didactic training in clinical trials and immunology, and mentorship by leaders in epidemiology, biostatistics, nephrology and immunology. She will draw on outstanding resources including the CHOP Research Institute and CTSA, the Center for Clinical Epidemiology and Biostatistics, and NEPTUNE. Her short-term goals are to: (1) dedicate 75% effort to this research and training program; (2) subsequently compete for NIH funds to support a trial of vitamin D supplementation and its impact on immune function and infectious complications in patients with glomerular diseases; and (3) expand the NEPTUNE study to relate baseline vitamin D levels and measures of mineral metabolism to cardiovascular disease, infections and renal disease progression. Her long-term goal is to lead an NIH-funded translational research program in children and adults with glomerular disease, with an emphasis on interventions to reduce complications and disease progression in this high-risk population. PUBLIC HEALTH RELEVANCE: Vitamin D deficiency has been linked to a variety of adverse health outcomes. Nephrotic patients have very low vitamin D levels, and the underlying mechanisms are not known. Furthermore, approaches to safely and effectively supplement vitamin D in these patients have not been established. The insights gained from this study are necessary to inform subsequent trials of vitamin D therapy to improve outcomes and develop unique supplementation guidelines for children and adults with diseases complicated by nephrotic syndrome.